US20090234005A1 - Protective agent for retinal neuronal cell containing prostaglandin f2alpha derivative as active ingredient - Google Patents

Protective agent for retinal neuronal cell containing prostaglandin f2alpha derivative as active ingredient Download PDF

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US20090234005A1
US20090234005A1 US11/887,037 US88703706A US2009234005A1 US 20090234005 A1 US20090234005 A1 US 20090234005A1 US 88703706 A US88703706 A US 88703706A US 2009234005 A1 US2009234005 A1 US 2009234005A1
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derivative
group
prostaglandin
cell
retinal neuronal
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US11/887,037
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Naruhiro Ishida
Atsushi Shimazaki
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Santen Pharmaceutical Co Ltd
AGC Inc
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Asahi Glass Co Ltd
Santen Pharmaceutical Co Ltd
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Assigned to ASAHI GLASS COMPANY LIMITED, SANTEN PHARMACEUTICAL CO., LTD reassignment ASAHI GLASS COMPANY LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ISHIDA, MARUHIRO, SHIMAZAKI, ATSUSHI
Publication of US20090234005A1 publication Critical patent/US20090234005A1/en
Assigned to ASAHI GLASS COMPANY, LIMITED reassignment ASAHI GLASS COMPANY, LIMITED CORPORATE ADDRESS CHANGE Assignors: ASAHI GLASS COMPANY, LIMITED
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a protective agent for a retinal neuronal cell containing a prostaglandin F2 ⁇ derivative as an active ingredient.
  • the retina is a tissue with a thickness of from 0.1 to 0.5 mm consisting of ten layers of inner limiting membrane, nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plexiform layer, outer nuclear layer, outer limiting membrane, photoreceptor cell layer and retinal pigment epithelium layer, and retinal neuronal cell groups including photoreceptor cells, bipolar cells, ganglion cells, horizontal cells, amacrine cells and Muller cells are present therein.
  • the retinal neuronal cells play an important role in the reception and transmission of visual information such as converting light stimulation into an electrical signal and transmitting the signal to the brain.
  • the visual information from the eyes is converted into an electrical signal through photoreceptor cells and transmitted to ganglion cells by way of horizontal cells, bipolar cells and/or amacrine cells. Then, the electrical signal is transmitted to the brain by way of the optic nerve which is a bundle of optic nerve fibers including axons of ganglion cells.
  • retinal neuronal cells when these retinal neuronal cells are damaged due to various causes, the homeostasis (a function to supply oxygen or nutrition to retinal neuronal cells through retinal blood circulation, and the like) of retinal neuronal cells cannot be maintained, and the transmission of visual information to the brain is inhibited.
  • dysfunction of retinal neuronal cells is caused in various retinal diseases such as retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, glaucoma, macular degeneration, retinitis pigmentosa and Leber's disease (Brain Res. Bull., 62(6), 447-453 (2004)).
  • retinal neuronal cell death due to retinal ischemia is one of the causes of retinal neuronal cell damage, and the following events have been reported regarding the retinal neuronal cell death due to retinal ischemia (JP-A-2003-146904 and Nature Rev., 2, 448-459 (2003)).
  • retinal neuronal cell death due to retinal ischemia is similar to that of cerebral neuronal cell death due to cerebral ischemia.
  • retinal inner layer In short term retinal ischemia, the retinal inner layer (inner plexiform layer) is selectively damaged.
  • NMDA retinal N-methyl-D-aspartate
  • a drug such as a glutamate neurotoxicity inhibitor, an NMDA receptor antagonist or an NO synthesis inhibitor is useful for treating an eye disease caused by retinal neuronal cell damage, and various studies have been carried out.
  • JP-A-2001-072591 discloses a protective agent for a retinal neuronal cell containing nipradilol which is one of the ⁇ -blockers as an active ingredient.
  • WO 01/056606 discloses a protective agent for an optic ganglion cell containing an interleukin-1 receptor antagonist protein as an active ingredient.
  • WO 03/004058 discloses a protective agent for an optic ganglion cell containing an ⁇ 1 receptor antagonist such as brimonidine hydrochloride as an active ingredient.
  • Experimental Eye Res., 72, 479-486 discloses a nerve-protecting effect of latanoprost which is one of the prostaglandin derivatives, etc.
  • prostaglandin F2 ⁇ derivatives are disclosed as a therapeutic agent for glaucoma having an intraocular pressure lowering action in JP-A-59-1418, JP-T-3-501025, JP-T-8-501310, JP-A-10-182465, WO 98/12175, European Patent Application Publication No. 850926, JP-A-2004-002462, JP-A-10-259179, JP-A-2002-293771 and JP-A-2003-321442.
  • JP-A-59-1418 discloses a natural prostaglandin F2 ⁇ derivative.
  • JP-T-3-501025 discloses a latanoprost-related compound.
  • JP-T-8-501310 discloses a bimatoprost-related compound.
  • JP-A-10-182465 discloses a travoprost-related compound.
  • WO 98/12175 discloses a monofluoroprostaglandin F2 ⁇ derivative.
  • European Patent Application Publication No. 850926 and JP-A-2004-002462 disclose a difluoroprostaglandin F2 ⁇ derivative.
  • JP-A-10-259179 discloses a fluorine-containing prostaglandin F2 ⁇ derivative having a multisubstituted aryloxy group.
  • JP-A-2002-293771 discloses an ether type difluoroprostaglandin F2 ⁇ derivative.
  • JP-A-2003-321442 discloses a difluoroprostaglandin F2 ⁇ amide derivative.
  • any of these documents does not describe an effect of a fluorine-containing prostaglandin F2 ⁇ derivative on protecting a retinal neuronal cell at all.
  • the present inventors made intensive studies in order to find a new pharmaceutical application of a prostaglandin F2 ⁇ derivative. As a result, they found that the prostaglandin F2 ⁇ derivative inhibits glutamate-induced retinal neuronal cell death in a concentration-dependent manner in rat fetal retinal neuronal cells, in other words, the prostaglandin F2 ⁇ derivative acts directly on the retinal neuronal cells and exhibits a protective effect, thus accomplished the present invention.
  • the present invention relates to a protective agent for a retinal neuronal cell containing a prostaglandin F2 ⁇ derivative as an active ingredient.
  • the present invention relates to a method of protecting a retinal neuronal cell and a method of preventing or treating an eye disease associated with retinal neuronal cell damage.
  • the “prostaglandin F2 ⁇ derivative” means a prostaglandin F2 ⁇ -related compound derived from the skeleton of prostanoic acid.
  • a protective agent for a retinal neuronal cell is, for example, one which contains a prostaglandin F2 ⁇ derivative or a salt thereof such as a natural prostaglandin F2 ⁇ derivative disclosed in JP-A-59-1418, a latanoprost-related compound (with the proviso that a latanoprost-related compound or a salt thereof excluding latanoprost) disclosed in JP-T-3-501025, a bimatoprost-related compound (preferably bimatoprost or a salt thereof) disclosed in JP-T-8-501310, a travoprost-related compound (preferably travoprost or a salt thereof) disclosed in JP-A-10-182465, or a fluorine-containing prostaglandin F2 ⁇ derivative disclosed in WO 98/12175, European Patent Application Publication No. 850926, JP-A-2004-002462, JP-A-10-259179, JP-A-2002
  • a protective agent for a retinal neuronal cell is, for example, one which contains a “fluorine-containing prostaglandin F2 ⁇ derivative” as an active ingredient.
  • the “fluorine-containing prostaglandin F2 ⁇ derivative” means a prostaglandin F2 ⁇ derivative having one or more fluorine atoms.
  • a protective agent for a retinal neuronal cell is, for example, one which contains a fluorine-containing prostaglandin F2 ⁇ derivative disclosed in WO 98/12175, European Patent Application Publication No. 850926, JP-A-2004-002462, JP-A-10-259179, JP-A-2002-293771 or JP-A-2003-321442 as an active ingredient.
  • a protective agent for a retinal neuronal cell is, for example, one which contains a 15,15-difluoroprostaglandin F2 ⁇ derivative disclosed in European Patent Application Publication No. 850926, JP-A-2004-002462, JP-A-10-259179, JP-A-2002-293771 or JP-A-2003-321442 as an active ingredient.
  • a further more preferred protective agent for a retinal neuronal cell is, for example, one which contains a 15,15-difluoroprostaglandin F2 ⁇ derivative represented by the following general formula (I), which is a further more preferred fluorine-containing prostaglandin F2 ⁇ derivative or a salt thereof, as an active ingredient.
  • a 15,15-difluoroprostaglandin F2 ⁇ derivative represented by the following general formula (I) which is a further more preferred fluorine-containing prostaglandin F2 ⁇ derivative or a salt thereof, as an active ingredient.
  • R represents a hydroxyalkyl group, a formyl group, a carboxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aminocarbonyl group, an alkylaminocarbonyl group or an arylaminocarbonyl group, and when R is an aryloxycarbonyl group or an arylaminocarbonyl group, the aryl moiety thereof may have a substituent.
  • R represents a hydroxyalkyl group, a formyl group, a carboxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aminocarbonyl group, an alkylaminocarbonyl group or an arylaminocarbonyl group, and when R is an aryloxycarbonyl group or an arylaminocarbonyl group, the aryl moiety thereof may have a substituent.
  • R represents a hydroxyalkyl group, a formyl group, a carboxy group, an alkoxy
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like.
  • alkoxy refers to straight-chain or branched alkoxy having 1 to 6 carbon atoms. Specific examples thereof include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy and the like.
  • aryl refers to monocyclic aromatic hydrocarbon, or bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms. Specific examples thereof include phenyl, naphthyl, anthryl, phenanthryl and the like.
  • aryloxy refers to monocyclic aromatic hydrocarbonoxy, or bicyclic or tricyclic condensed polycyclic aromatic hydrocarbonoxy having 6 to 14 carbon atoms. Specific examples thereof include phenoxy, naphthyloxy, anthryloxy, phenanthryloxy and the like.
  • alkylamino refers to monoalkylamino or dialkylamino having 1 to 12 carbon atoms. Specific examples thereof include methylamino, ethylamino, dimethylamino, dihexylamino and the like.
  • arylamino refers to monoarylamino or diarylamino having 6 to 28 carbon atoms. Specific examples thereof include phenylamino, naphthylamino, methylphenylamino, ethylphenylamino, diphenylamino, dianthrylamino and the like.
  • R is an “aryloxycarbonyl group” or an “arylaminocarbonyl group”
  • the aryl moiety thereof may have a substituent.
  • the substituent an atom or a group selected from a halogen atom, an alkyl group, a halogenated alkyl group and an alkoxy group is preferred, and the number of the substituents is preferably 1 to 3.
  • a further more preferred fluorine-containing prostaglandin F2 ⁇ derivative is, for example, a 15,15-difluoroprostaglandin F2 ⁇ derivative of the above-mentioned general formula (I) in which R represents a carboxy group or a salt group thereof or an alkoxycarbonyl group.
  • a particularly preferred fluorine-containing prostaglandin F2 ⁇ derivative is, for example, a 15,15-difluoroprostaglandin F2 ⁇ derivative of the above-mentioned general formula (I) in which R represents a carboxy group or a salt group thereof or an isopropoxycarbonyl group.
  • another preferred compound is, for example, a 15-monofluoroprostaglandin F2 ⁇ derivative described in the above-mentioned WO 98/12175.
  • prostaglandin F2 ⁇ derivatives can be in the form of a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid, an organic acid such as acetic acid, fumalic acid, maleic acid, succinic acid or citric acid, an alkali metal such as lithium, sodium or potassium, an alkaline earth metal such as calcium or magnesium, ammonia or the like.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid
  • an organic acid such as acetic acid, fumalic acid, maleic acid, succinic acid or citric acid
  • an alkali metal such as lithium, sodium or potassium
  • an alkaline earth metal such as calcium or magnesium, ammonia or the like.
  • the “retinal neuronal cell” means a neuronal cell involved in the transmission of visual signal to the brain. Specifically, it means a photoreceptor cell, a horizontal cell, a bipolar cell, an optic ganglion cell, an amacrine cell or the like.
  • the “eye disease” means an eye disease associated with retinal neuronal cell damage.
  • abnormal visual field retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, glaucoma, macular degeneration, retinitis pigmentosa, Leber's disease or the like
  • abnormal visual field retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa or Leber's disease.
  • the protective agent for a retinal neuronal cell of the present invention can be administered orally or parenterally.
  • the dosage form for administration include an eye drop, an ophthalmic ointment, an injection, a tablet, a capsule, a granule, a powder, and the like, and particularly preferred is an eye drop.
  • Such a preparation can be prepared by any of widely used techniques, for example, a technique disclosed in JP-A-59-1418, JP-T-3-501025, JP-T-8-501310, JP-A-10-182465, WO 98/12175, European Patent Application Publication No. 850926, JP-A-2004-002462, JP-A-10-259179, JP-A-2002-293771, JP-A-2003-321442, WO 2/22131 or the like.
  • an eye drop can be prepared using a tonisity agent such as sodium chloride or concentrated glycerin, a buffer such as sodium phosphate or sodium acetate, a surfactant such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate or polyoxyethylene hydrogenated castor oil, a stabilizer such as sodium citrate or sodium edetate, a preservative such as benzalkonium chloride or paraben according to need.
  • a tonisity agent such as sodium chloride or concentrated glycerin
  • a buffer such as sodium phosphate or sodium acetate
  • a surfactant such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate or polyoxyethylene hydrogenated castor oil
  • a stabilizer such as sodium citrate or sodium edetate
  • a preservative such as benzalkonium chloride or paraben according to need.
  • the pH of the eye drop is permitted as long as it falls within the range that is acceptable
  • An ophthalmic ointment can be prepared using a widely used base such as white soft paraffin or liquid paraffin according to need.
  • an oral preparation such as a tablet, a capsule, a granule or a powder
  • an extender such as lactose, crystalline cellulose, starch or a vegetable oil, a lubricant such as magnesium stearate or talc, a binder such as hydroxypropyl cellulose, or polyvinylpyrrolidone, a disintegrant such as carboxymethyl cellulose calcium or low-substituted hydroxypropylmethyl cellulose, a coating agent such as hydroxypropylmethyl cellulose, macrogol or a silicone resin, a film forming agent such as gelatin film, or the like according to need.
  • an extender such as lactose, crystalline cellulose, starch or a vegetable oil
  • a lubricant such as magnesium stearate or talc
  • a binder such as hydroxypropyl cellulose, or polyvinylpyrrolidone
  • a disintegrant such as carboxymethyl cellulose calcium or low-substitute
  • the dose can be appropriately selected depending on the symptoms, age, dosage form and the like.
  • An eye drop may be instilled once to several times a day at a concentration of from 0.00001 to 1% (w/v), preferably from 0.0001 to 1% (w/v).
  • An oral preparation may be administered once or divided into several times at a dose of generally from 0.01 to 5000 mg per day, preferably from 0.1 to 1000 mg per day.
  • the prostaglandin F2 ⁇ derivative inhibited the glutamate-induced retinal neuronal cell death in a concentration-dependent manner. That is, the prostaglandin F2 ⁇ derivative has an action of protecting a retinal neuronal cell, and is useful for the prevention or treatment of an eye disease associated with retinal neuronal cell damage.
  • a desired eye drop can be obtained by appropriately changing the kinds and the amounts of the prostaglandin F2 ⁇ derivative and additives.
  • a desired ophthalmic ointment can be obtained by appropriately changing the kinds and the amounts of the prostaglandin F2 ⁇ derivative and additives.
  • prostaglandin F2 ⁇ derivative which is a test compound
  • 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor-prostaglandin F2 ⁇ was used.
  • a pregnant SD rat was subjected to laparotomy under systemic anesthesia, and the uterus was transferred to a dish containing Hanks's balanced salt solution (HBSS).
  • HBSS Hanks's balanced salt solution
  • a rat fetus was isolated from the uterus, and the eyeballs of the rat fetus were taken out.
  • the retina was isolated from the eyeballs under a stereoscopic microscope and cut into pieces with a surgical knife. Then, the retina was further broken down to the cellular level and passed through a nylon mesh (No. 305, manufactured by NBC Industries Co., Ltd.) to remove cell aggregates, and then, the resulting filtrate was centrifuged at 1000 rpm for 4 minutes.
  • a nylon mesh No. 305, manufactured by NBC Industries Co., Ltd.
  • the supernatant was removed, and an appropriate amount of a modified Eagle's medium (MEM) containing 10% fetal bovine serum (FBS) was added to the remaining cells to suspend them. After the cell number was counted with a hemocytometer, an MEM medium containing 10% FBS was added thereto, whereby a cell suspension with a cell density of 0.8 ⁇ 10 6 cells/mL was obtained.
  • the cell suspension was inoculated in an amount of 80 ⁇ L each into polyethylenimine-coated plastic discs, and the discs were allowed to stand in an incubator (37° C., 5% CO 2 ). The day of cell inoculation was designated as day 1 of culture, and medium replacement was carried out on even number days.
  • MEM modified Eagle's medium
  • FBS fetal bovine serum
  • an MEM medium containing 10% FBS was used, and after day 8, an MEM medium containing 10% horse serum (HS) was used.
  • an MEM medium containing 10% horse serum (HS) was used on day 6, 6 mL of a medium containing cytarabine (Ara-C) (1.5 ⁇ 10 ⁇ 5 M in an MEM medium containing 10% FBS) was used for removing proliferative cells.
  • test compound 2 mg was dissolved in 100% ethanol, and the resulting solution was sequentially diluted with an HS-containing MEM medium, whereby an HS-containing MEM medium containing the test compound at 0.1 nM, 1 nM, 10 nM or 100 nM was prepared.
  • test compound 2 mg was dissolved in 100% ethanol, and the resulting solution was sequentially diluted with a serum-free MEM medium, whereby a serum-free MEM medium containing the test compound at 0.1 nM, 1 nM, 10 nM or 100 nM was prepared.
  • the plastic discs in which cells were inoculated and cultured were transferred to the HS-containing MEM medium containing the test compound and incubated for 24 hours (37° C., 5% CO 2 ).
  • the plastic discs were transferred to a serum-free MEM medium containing 1 mM glutamate and incubated for 10 minutes, and then transferred to the serum-free MEM medium containing the test compound and incubated for 1 hour (37° C., 5% CO 2 ).
  • the cells were stained with a 1.5% trypan blue solution for 10 minutes and fixed by adding a 10% formalin fixative solution thereto. After the cells were washed with a physiological saline solution, stained cells and unstained cells were counted under an inverted microscope.
  • a vehicle administration group was prepared by carrying out the same test as described above except that an HS-containing MEM medium was used instead of the above-mentioned HS-containing MEM medium containing the test compound and a serum-free MEM medium was used instead of the above-mentioned serum-free MEM medium containing the test compound.
  • an untreated group was prepared by carrying out the same test as described above except that an HS-containing MEM medium was used instead of the above-mentioned HS-containing MEM medium containing the test compound and a serum-free MEM medium was used instead of the above-mentioned serum-free MEM medium containing the test compound, and further a treatment with a serum-free MEM medium containing glutamate was not carried out.
  • the survival rate was calculated based on the following calculation equation.
  • FIG. 1 is a graph showing the survival rate for each concentration in the case of using the test compound by the addition of glutamate.

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PCT/JP2006/306826 WO2006106915A1 (ja) 2005-03-31 2006-03-31 プロスタグランジンＦ2α誘導体を有効成分として含む網膜神経細胞保護剤

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US20120014970A1 (en) * 2009-01-09 2012-01-19 Reza Dana Therapeutic Compositions for Treatment of Corneal Disorders
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WO2008133021A1 (ja) * 2007-04-12 2008-11-06 R-Tech Ueno, Ltd. プロスタグランジンＦ２α化合物を有効成分として含む視神経障害改善剤組成物
KR101628415B1 (ko) * 2008-09-04 2016-06-08 산텐 세이야꾸 가부시키가이샤 15,15-디플루오로프로스타글란딘 Ｆ2α 유도체를 유효 성분으로서 함유하는 모발 성장 촉진제
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US9820993B2 (en) 2013-05-15 2017-11-21 Topokine Therapeutics, Inc. Methods and compositions for topical delivery of prostaglandins to subcutaneous fat
WO2015200425A1 (en) 2014-06-27 2015-12-30 Topokine Therapeutics, Inc. Topical dosage regimen

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US9138438B2 (en) 2015-09-22
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EP1864666A4 (en) 2008-04-02
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CA2602573A1 (en) 2006-10-12

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